1-allyl-4-phenyl-4-carbalkoxy-piperidines and their acid addition salts



United States Patent O 4 PHENYL 4 CARBALKOXY PI- ACE) ADDITION SALTS andKurt Freter, Ingelheim (Rhine), Ger-may, assignors to BoehringerIngelheim Gesellschaft mit beschrankter Haftung, Ingelheim (Rhine),Germany, a corporation of Germany N Drawing. Filed May 27, 1963, Ser.No. 283,547

5 Claims. (Cl. 269-2943) 1 ALLYL PEREDHQES AND THEIR Karl Zeile, HerbertMerz,

This is a continuation-in-part of copending applications Serial Nos.174,412 and 174,386, each filed February 20, 1962, both now abandoned.

This invention relates to novel piperidine derivatives and their acidaddition salts, as well as to methods of preparing these piperidinecompounds and their acid addition salts.

More particularly, the present invention relates to the1-allyl-4-phenyl-4-carbalkoxy-piperidines of the formula 0 i ii-onon,=ononrnai +HHal 150 C. The reagents may be reacted with each other attemperatures between 50 and ice in a molar relationship of 1:1.Preferably, however, the allyl halide is used in excess.

Method B.-Reaction of a 3-phenyl-3-carbalkoxy-1,5- dihalopentane withallylamine according to the following reaction formula 2H Hal GHFCH=CHIwherein R has the meanings previously defined and Hal is a halogen,preferably chlorine or bromine.

The reaction is preferably carried out. in an inert or- [1 /CEN O GEN9H2 T Hal Hal 2H Hal H2 H2 on, on,

\ on -on=on,

wherein Hal is a halogen, preferably chlorine or bromine.

The reaction is preferably carried out in the presence of powderedsodium amide and in an inert organic solvent, such as toluene, attemperaturesbetween 50 and 200 C. Thereafter, the resulting1-allyl-4-cyano-4- phenyl-piperidine is reacted with hydrogen bromide toconvert the cyano group into a free carboxyl group. The resulting1-allyl-4-phenyl-4-carboxy-piperidine hydrobromide is esterified withmethanol or propanol in the presence of concentrated sulfuric acid toyield the desired 1-allyl-4-phenyl-4-carbalkoxy-piperidine hydrobromide.

The free l-allyl-4-phenyl-4-carbalkoxy-piperidines obtained pursuant toMethods A and B may, if desired, be transformed into their non-toxicacid addition salts by customary methods, that is, by acidification withthe appropriate acid having a non-toxic anion. Similarly, thehydrobromide obtained pursuant to Method C may, if desired, betransformed into other non-toxic acid addition salts by acidificationwith the appropriate acid having a non-toxic anion. In addition tohydrobromic acid, ex-

benzylcyanide with a tertiary panied by stirring.

EXAMPLE I Preparation of I-Allyl-4-Phenyl-4-Carb0methoxy-' Piperidineandits Hydrobromide 2.2 gm. (0.010 mol) of4-phenyl-4-carbomethoxypiperidine. were dissolved in 20 ml. of ethanol.0.95 gm; (0.011 mol) of sodium bicarbonate and 1.33 gm. (0.011 mol) ofallyl bromide were added to the resultingsolution, and the mixture wasrefluxed for one hour, accompanied by stirring. After cooling, thealcoholic reaction solution was filtered and the alcoholwas evaporatedin vacuo. The evaporation residue, which consisted of l-allyl-4-phenyl-4-carbomethoxy-piperidine having a boiling point of about 150C./0.l mm. Hg was acidified with Q N hydrobrornic acid. Thehydr'obromide of 1-allyl-4-phenyl- .4-carbomethoxy-piperidineprecipitated out. ,After recrystallization of theprecipitate from water,3.05 gm.

.(90% of the theoretical amount) of l-allyl-4-phenyl-4-'carbomethoxy-piperidine hydrobromide were obtained. The product had amelting point of 209-211" C. and the formula 0 t ii-ocn l onz-onrnniEXAMPLE II 7 Preparation of I-Allyl-4-Phenyl-4-Carbopropoacy- Piperidineand its Hydrobromide 2.4 gm. (0.010 mol) of4-phenyl-4-carbopropoxypiperidine were dissolved in ml. of ethanol. 0.95gm.

7 (0.011 mol). of sodium bicarbonate and 1.21 gm. (0.010

mol) of allyl bromide were added to the resulting solution, and themixture was refluxed for one hour, accom- After cooling, the alcoholicreaction solution-was filtered and the alcohol was evaporated in vacuo..The evaporation residue, which consisted of 1-allyl-4-phenyl-4-carbopropoxy-piperidine having a boiling .pointof about170 C./0.1 mm. Hg was acidified with 2 N hydrobromic acid. Thehydrobromide of 1-allyl-4- phenyl-4-carbopropoxy-piperidine precipitatedout. After recrystallization of the precipitate from water, 3.3 gm.(9.0% of the theoretical amount) of l-allyl-4-phenyl-4-.carbopropoxy-piperidine hydrobromide .were obtained. The product had amelting point of 149-15Ov C. and the formula piperidin'e compounds ofthe present invention and their The l-allyl 4-phenyl-4-carbalkoxypiperidines' of the Formula I above and their non-toxic,-pharmacologically acceptable acidyaddition salts have usefulpharmacodynarnic properties. More particularly, the compounds accordingto the present invention exhibit highly efiective analgesic activitiesand at the same time pronounced morphine-antagonistic efiects. Thus,they exhibit pharmacodynamic activities which are unexpectedly andsurprisingly different in kind from those of the adjacent homologl-allyl-4-phenyl-4-carbethoxy-piperidine' hydrochloride described by D.J. Costa and D. D. Bonnycastle in Journal of Pharmacology andExperimental Therapeutics, vol. 113, pp. 310 et seq. (1955). The priorart compound exhibits no morphine-antagonistic activity whatsoever and avery low analgesic activity.

The high morphine-antagonistic activity of the l-allyi-4-phenyl-4-carbalkoXy-piperidinesof the present invention is eifectivelydemonstrated by the following pharmae cological tests. A statisticallysignificant nunibe'rof adult white mice were administered 15 mgnm/kg.body weight of morphine by injection, that is, the ED of morphine (dosewhich produces an analgesic efl'ect in 50% of the mice, as determinedbythe Hafiner method). Thereafter, the mice were injected with varyingamounts of 1-allyl-4- pheny1-4-carbomethoxy-piperidine hydrobromide andthe corresponding 4-carbopropoxy compound, respectively. After a shorttime interval to allow the injections to take effect, the mice weretested for detectable analgesia. The following tables show the results.

TABLE I Percentage of mice with detectable analgesia, percent amount of1-a1ly1-4-phenyl-4-earb'ornethoxy-piperidine hydrobromido injected,mgmJkg. body weight Col- 01 TABLE II Percentage of mice with detectableanalgesia, percent Amount or l-allyl-i-phenyl-t-carbopropoxy-pipcridinehydrobromide injected, per kg. body weight None of the animals showedany evidence of toxic symptomsincident to analgesic doses of morphine.Moreover, all animals survived a subcutaneous injection of 200 mgrn./kg.of l-allyl-4-phenyl-4-carbopropoxy-piperidine hydrobrornide or1-allyl-4-phenyl-4-carbomethoxypiperidine hydrobromide without toxic.symptoms.

By virtue of this morphine-antagonistic activity, the

non-toxic acid addition salts maybe employed in conjunction with knowncentral analgesics, such as morphine, meperidine methadone, to preventrespiratory depression Without interference with the analgesic effects.

For this purpose the piperidine compounds according to the presentinvention or their non-toxic acid addition salts may, for instance, beincorporated into injectable isotonic solutions of morphine, meperidine,methadone or the like in amounts of 0.010.1 mgm. per mL'Of solu-However, the piperidine compoundsof the present 7 tion. invention ortheir non-toxic acid addition salts may also be used as the soleanalgesic ingredients in conjunction with an inert carrier in a dosageunit composition, such as a sterile, injectable isotonic solution inampules.

Under these circumstances, the effective dosage of the piperidinecompounds or their acid addition salts is also from 0.01-0.1 gm.

The following are illustrative examples of dosage unit hypodermicsolutions in ampule form comprising a nontoxic acid addition salt of1-allyl-4-phenyl-4-carbopropoxy-piperidine or 1 allyl 4phenyl-4-carbomethoxypiperidine as the morphine-antagonistic ingredient:

Mgm. 1-allyl-4-phenyl-4-carbopropoxy piperidine hydrobromide 0.1Morphine-HCl 20.0 0.001 N HCl, q.s. ad. 1 rnl.

Mgm. 1-a1lyl-4-phenyl-4-carbopropoxy-piperidine hydrobromide 0.05Meperidine hydrochloride 100.00 Distilled water, q.s. ad. 2 ml.

Mgm. 1-ally1-4-phenyl-4-carbopropoxy piperidine hydrobromide 0.1Methadone hydrochloride 10.0 Distilled water, q.s. ad. 2 ml.

Mgrn. 1-allyl-4-phenyl-4-carbomethoxy piperidine hydrobromideMorphine-HCl 20.0 0.001 N HCl, q.s. ad. 1 ml.

Mgm. 1-allyl-4-phenyl-4-carbomethoxy-piperidine hydrobromide Meperidinehydrochloride 100.0

Distilled water, q.s. ad. 2 ml.

Mgm. 1-allyl-4-phenyl 4 carbomethoxy-piperidjne hydrobromide 0.5Methadone hydrochloride 5.0

Distilled Water, q.s. ad. 1 m1.

While we have illustrated our invention with the aid of certain specificembodiments, it will be readily apparent to those skilled in the artthat the present invention is not limited to these specific embodimentsand that various changes and modifications may be made without departingfrom the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound selected from the group consisting ofl-allyl-4-phenyl-carbalkoxy-piperidines of the formula wherein R isselected from the group consisting of methyl and propyl, and theirnon-toxic, pharmaceutically acceptable acid addition salts.

2. 1-allyl-4-pheny1-4-carbomethoxy-piperidine.

3. 1-allyl-4-pheny1-4-carbomethoxy piperidine hydrobromide.

4. 1-allyl-4-phenyl-4-carbopropoxy-piperidine.

5. 1-a1ly1-4-phen'yl 4 carbopropoxy-piperdine hydrobromide.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,135,760 June 2, 1964 Karl Zeile et al.

hat error appears in the above numbered pat- It is hereby certified t sPatent should read as ent requiring correction and that the said Lettercorrected below.

Column 6, line 16, for carloalkoxy-" read -4carbalk0xy lines 18 to 23,the formula should appear as shown below instead of as in the patent:

l ca CH:CH

Signed and sealed this 3rd day of November 1964.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J, BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF1-ALLYL-4-PHENYL-CARBALKOXY-PIPERIDINES OF THE FORMULA